Novel and Emerging LDL-C Lowering Strategies: A New Era of Dyslipidemia Management

Abstract

Atherosclerotic cardiovascular disease (ASCVD) represents a major global health challenge, significantly contributing to mortality rates. This chronic inflammatory condition affecting blood vessels is intricately linked to hypercholesterolemia, with elevated levels of low-density lipoprotein cholesterol (LDL-C) recognized as a central and modifiable risk factor. The effectiveness of lipid-lowering therapy (LLT) in mitigating ASCVD risk is well established, with studies revealing a substantial reduction in major ischemic events correlating with LDL-C reduction. While statins, often combined with ezetimibe, remain fundamental in dyslipidemia management, a significant proportion of patients on statin therapy continue to experience cardiovascular events. Recent pharmacological advancements, driven by a deeper understanding of atherogenesis, have unveiled novel therapeutic targets and potent drugs. Notably, agents like bempedoic acid and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab, inclisiran) have emerged as effective options to intensify LLT and achieve LDL-C goals, addressing limitations associated with statins, such as myopathy. Molecular insights into alternative pathways have spurred the investigation of emerging agents, offering promising perspectives for novel medications with efficacy comparable to established treatments, associated with advantages in cost and administration. This review provides a comprehensive overview of the evolving landscape of lipid-lowering strategies, highlighting the progress made in addressing ASCVD risk and the potential of upcoming therapies to further optimize cardiovascular prevention.

Keywords: ACS; LDL-C; PCSK9i; bempedoic acid; dyslipidemia; statin.

Figure 1

LDL-C goals evolution across guidelines over time. The timeline illustrates the evolution of LDL-C targets over time, reporting the recommended LDL-C goal across the different guidelines. The Adult Treatment Panel I (ATP I) guidelines in 1988 first deemed a desirable LDL-C target of 130 for all individuals at risk of ASCVD in primary prevention. Afterward, specific LDL-C cutoffs were established for secondary and primary prevention based on risk categories. These goals have become progressively stringent over time, culminating in the 2019 ESC guidelines, which underline a particularly lower LDL-C goal of 40 mg/dL for patients with repeated events within 2 years (silver marker). In the figure, the color marker represents the class of ASCVD risk (green for low risk, yellow for moderate risk, red for high risk and violet for very high risk respectively), while the very high risk is indicated in the box. The ATP I outlined an LDL-C target for all individuals (blue marker), independently of risk categories. Abbreviations: AACE, American Association of Clinical Endocrinologists; ATP, Adult Treatment Panel; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; LDL-C, low-density lipoprotein cholesterol.

Figure 2

Proposed algorithm to manage LDL-C in patients with acute coronary syndrome. The figure illustrates the algorithm to control LDL-C in adult patients with ACS, as proposed by the authors. The therapeutic decision during hospitalization is guided by the presence or absence of prior LLT and the percentage reduction of LDL-C required to achieve the LDL-C goal of <55 mg/dL. At one-month reassessment, potential further optimization of therapy is indicated if the target has not been met. In the figure, “statin” refers to high-intensity statin therapy at the maximum tolerated dose. PCSK9i refers to one of the available drugs of this class (mAbs or siRNA, independently); thus, in case of intolerance or non-responsiveness, a switch to a different PCSK9i may be considered. The orange color, near the symbol indicating statin intolerance, highlights alternative therapeutic strategies to statins. The combination of these alternatives is guided by considering the LDL-C values at the baseline and the necessary percentage reduction to reach the target. The algorithm ensures a personalized approach to LLT, considering the patient’s prior treatment history and the individualized goal for LDL-C reduction. Abbreviations: ACS, acute coronary syndrome; LDL-C, low-density lipoprotein cholesterol; N = not; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors; Y = yes.